The candidate for this K24:Mid Career Investigator in Patient Oriented Research is an experienced and productive physician-scientist whose work has concentrated upon autoimmune rheumatic diseases, including systemic lupus erythematosus. The candidate has made important contributions to the understanding of SLE pathogenesis, including genetic. He carries out this work in the Arthritis & Immunology Program at Oklahoma Medical Research Foundation, one of the largest and most productive research units dedicated to the study of immune-mediated rheumatic illness. SLE is complicated, with a wide range of manifestations. Use of stratification of a disease population has proven very useful in other diseases (BCR1 gene, for example). We hypothesize (and the preliminary data demonstrate) that the clinical phenotypes of SLE are valuable in uncovering the genetics of SLE. Thrombocytopenia predicts severe disease and death in SLE, making the identification of related genetic risk factors especially important. We selected the 38 pedigrees that had an SLE patient with thrombocytopenia from 179 pedigrees multiplex for SLE. Linkage was established at 11p13 (Iod=5.72) in the 13 African-American pedigrees. Nephritis, serositis, europsychiatric involvement, autoimmune hemolytic anemia, anti-double stranded DNA and antiphospholipid antibody were associated with thrombocytopenia. SLE is more severe in the families with a thrombocytopenic SLE patient, whether or not thrombocytopenia in an individual patient is considered. This project will explore the genetics of the severe phenotype of SLE defined by thrombocytopenia. In particular, the PI will concentrate on the statistically powerful finding on chromosome 11p13, the strongest found to date in SLE. In the first specific aim, the genetic interval will be fine mapped with DNA microsatellite markers in order to confirm linkage and narrow the interval. In Specific Aim 2 the PI will search for genetic association with SLE by typing at single nucleotide polymorphisms throughout the defined interval supporting linkage. In Specific Aim 3, the genetic polymorphism(s) responsible for the linkage will be sought by sequencing genes within the now narrowly defined linkage interval. Finally, Specific Aim 4 will assemble a new cohort of families multiplex for SLE so that linkages and associations as well as particular polvmorphisms can be prospectively confirmed.